Maternal bile acid transporter deficiency promotes neonatal demise

Yuanyuan Zhang, Fei Li, Yao Wang, Aaron Pitre, Zhong-ze Fang, Matthew W. Frank, Christopher Calabrese, Kristopher W. Krausz, Geoffrey Neale, Sharon Frase, Peter Vogel, Charles O. Rock, Frank J. Gonzalez and John D. Schuetz ()
Additional contact information
Yuanyuan Zhang: St Jude Children's Research Hospital
Fei Li: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
Yao Wang: St Jude Children's Research Hospital
Aaron Pitre: St Jude Children's Research Hospital
Zhong-ze Fang: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
Matthew W. Frank: St Jude Children's Research Hospital
Christopher Calabrese: Small Animal Imaging Core, St Jude Children’s Research Hospital
Kristopher W. Krausz: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
Geoffrey Neale: Hartwell Center, St Jude Children's Research Hospital
Sharon Frase: Cellular Imaging Shared Resource, St Jude Children’s Research Hospital
Peter Vogel: St Jude Children's Research Hospital
Charles O. Rock: St Jude Children's Research Hospital
Frank J. Gonzalez: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
John D. Schuetz: St Jude Children's Research Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition.

Date: 2015
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DOI: 10.1038/ncomms9186

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